RESUMEN
High activity of histone deacetylases (HDACs) causes epigenetic alterations associated with malignant cell behaviour. Consequently, HDAC inhibitors have entered late-phase clinical trials as new antineoplastic drugs. However, little is known about expression and function of specific HDAC isoforms in human tumours including prostate cancer. We investigated the expression of class I HDACs in 192 prostate carcinomas by immunohistochemistry and correlated our findings to clinicopathological parameters including follow-up data. Class I HDAC isoforms were strongly expressed in the majority of the cases (HDAC1: 69.8%, HDAC2: 74%, HDAC3: 94.8%). High rates of HDAC1 and HDAC2 expression were significantly associated with tumour dedifferentiation. Strong expression of all HDACs was accompanied by enhanced tumour cell proliferation. In addition, HDAC2 was an independent prognostic marker in our prostate cancer cohort. In conclusion, we showed that the known effects of HDACs on differentiation and proliferation of cancer cells observed in vitro can also be confirmed in vivo. The class I HDAC isoforms 1, 2 and 3 are differentially expressed in prostate cancer, which might be important for upcoming studies on HDAC inhibitors in this tumour entity. Also, the highly significant prognostic value of HDAC2 clearly deserves further study.
Asunto(s)
Histona Desacetilasas/metabolismo , Neoplasias de la Próstata/enzimología , Anciano , Estudios de Cohortes , Histona Desacetilasa 1 , Histona Desacetilasa 2 , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Antígeno Prostático Específico/análisis , Prostatectomía , Proteínas Represoras/metabolismo , Análisis de SupervivenciaRESUMEN
Activation of nuclear factor-kappaB (NF-kappaB) signaling was observed in pancreatic adenocarcinoma cell lines and tumours. However, information on the expression of RelA/p65, the major transcription activating NF-kappaB subunit, in these carcinomas and possible correlations thereof with NF-kappaB activation and patient survival is not available. To provide this missing translational link, we analysed expression of RelA/p65 in 82 pancreatic adenocarcinomas by immunohistochemistry. Moreover, we measured activation of the NF-kappaB pathway in 11 tumours by quantitative PCR for NF-kappaB target genes. We observed strong cytoplasmic or nuclear expression of RelA/p65 in 42 and 37 carcinomas, respectively. High cytoplasmic and nuclear expression of RelA/p65 had negative prognostic impact with 2-year survival rates for patients without cytoplasmic or nuclear RelA/p65 positivity of 41 and 40% and rates for patients with strong cytoplasmic or nuclear RelA/p65 expression of 22 and 20%, respectively. High RelA/p65 expression was correlated to increased expression of NF-kappaB target genes. The observation that high expression of RelA/p65 is correlated to an activation of the NF-kappaB pathway and indicates poor patient survival identifies a patient subgroup that might particularly benefit from NF-kappaB-inhibiting agents in the treatment of pancreatic cancer. Based on our findings, this subgroup could be identified by applying simple immunohistochemical techniques.
Asunto(s)
Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , FN-kappa B/metabolismo , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Factor de Transcripción ReIA/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Persona de Mediana Edad , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidad , Pronóstico , Transducción de Señal , Análisis de Supervivencia , Factor de Transcripción ReIA/metabolismoRESUMEN
AIMS: NF-kappaB has been demonstrated to activate proliferative, inflammatory, and angiogenic processes in ovarian cancer cells in vitro. To add translational information on the situation in vivo, we determined the expression pattern of p65, an important subunit of the classic NF-kappaB pathway, in ovarian carcinoma tissue, and investigated in vivo and in vitro whether this pathway is implicated in the known overexpression of cyclooxygenase-2 (COX-2). METHODS: p65 siRNA, chemiluminescent NF-kappaB transcription factor assay, Taqman PCR, as well as immunoblotting were performed with OVCAR-3 ovarian cancer cells. 83 primary ovarian cancinomas as well as 17 cases of benign ovarian tissue were analyzed by p65 and COX-2 immunohistochemistry using a tissue microarray. RESULTS: DNA-binding avtivity as well as COX-2 mRNA and protein expression were strongly inducible by IL-1beta treatment in OVCAR-3 cells, while p65 siRNA inhibited IL-1beta-dependent p65 activity (p = 0.037) as well as COX-2 expression on the mRNA (p < 0.03) and on the protein level. In human tumor tissue, p65 protein expression was significantly associated with COX-2 expression (p = 0.002) as well as tumor grading (p = 0.005). Furthermore, p65 expression was a significant prognostic indicator of a reduced patient survival both in univariate (p = 0.038) and in multivariate analysis (p = 0.014). CONCLUSION: Our study indicates a deregulation of the classical NF-kappaB pathway in ovarian cancer, which results in the overexpression of the NF-kappaB target gene COX-2. Components of this pathway might constitute novel attractive targets for a specific therapy of advanced ovarian cancer.
Asunto(s)
Ciclooxigenasa 2/genética , Neoplasias Ováricas/genética , Factor de Transcripción ReIA/genética , Antineoplásicos/uso terapéutico , Femenino , Humanos , Inmunohistoquímica , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/enzimología , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Polimorfismo Conformacional Retorcido-Simple , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas c-mdm2/genética , Receptores de Estrógenos/análisis , Análisis de Supervivencia , Proteína p53 Supresora de Tumor/genéticaRESUMEN
We describe a case of a 41-year-old female patient who was admitted with typical signs of thrombotic-thrombocytopenic purpura. Markers of myocardial ischemia (Troponin T, CK, CK-MB) were even present at admission without symptoms of angina pectoris. Only a few hours after admission the patient developed all signs of cardiogenic shock with subsequently cardiac arrest. Postmortal coronary angiographies showed occlusions in all coronary arteries with significant myocardial necrosis. We are unaware of any report that describes macrovascular occlusions in thrombotic-thrombocytopenic purpura.
Asunto(s)
Trombosis Coronaria/etiología , Miocardio/patología , Púrpura Trombocitopénica Trombótica/complicaciones , Adulto , Trombosis Coronaria/diagnóstico , Femenino , Paro Cardíaco/etiología , Humanos , Necrosis , Choque Cardiogénico/etiologíaRESUMEN
A rare case of a primary fibrosarcoma of the liver infiltrating the right heart is described in a 72-year-old woman. The patient presented with a history of progressive dyspnea and ascites and her general condition was poor. Preoperative cardiac magnetic resonance (CMR) imaging revealed a large mass, which originated from the liver and had infiltrated the right atrium via the inferior vena cava. The patient underwent tumor resection yet died shortly afterwards. Histologically the mass was classified as a fibrosarcoma with positive immunostaining for vimentin. We report the CMR imaging characteristics in this uncommon case. Preoperative CMR proved to be useful for clinical decision making and the planning of surgery.
Asunto(s)
Fibrosarcoma/diagnóstico , Atrios Cardíacos/patología , Neoplasias Cardíacas/patología , Neoplasias Hepáticas/patología , Anciano , Disnea/etiología , Resultado Fatal , Femenino , Humanos , Imagen por Resonancia Magnética , Invasividad NeoplásicaRESUMEN
Lysophosphatidic acid acyltransferase beta (LPAAT-beta) is an enzyme involved in lipid biosynthesis whose role in tumour progression has been of emerging interest in the last few years. We investigated the expression of LPAAT-beta by reverse transcriptase-polymerase chain reaction and immunohistochemistry in 10 ovarian cell lines as well as in a cohort of 106 ovarian tumours and normal ovaries. Lysophosphatidic acid acyltransferase beta mRNA was found in all cell lines and ovarian tumours examined. Expression of LPAAT-beta protein was significantly increased in ovarian carcinomas compared to benign ovarian tissue (chi2 test P-value=0.001, Kruskal-Wallis test P-value <0.0001). Furthermore, LPAAT-beta expression was positively associated with higher tumour grade (P=0.044), higher mitotic index (P<0.0001) and tumour stage (P=0.032). Expression of LPAAT-beta was significantly linked to reduced overall survival time (P=0.024) as well as to shorter progression-free survival time (P=0.012) in patients younger than 60 years. Our study shows that LPAAT-beta is upregulated in ovarian cancer and is more prevalent in poorly differentiated tumours. In addition, LPAAT-beta expression is a predictor of a worse prognosis in patients younger than 60 years. Further studies are needed to investigate if LPAAT-beta may serve as a therapeutic target for certain subgroups of patients.
Asunto(s)
Aciltransferasas/metabolismo , Carcinoma/metabolismo , Neoplasias Ováricas/metabolismo , Carcinoma/patología , Línea Celular Tumoral , Femenino , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/patología , Ovario/metabolismo , Pronóstico , Análisis de SupervivenciaRESUMEN
The distribution of gene variants of the antigen processing proteins transporter associated with antigen processing type 1 (TAP1) and proteasome subunit beta type 9 (PSMB9) and of their shared bidirectional promoter was assessed in children with either mild or severe malaria. The genetic study was performed on samples collected during a longitudinal study on malariometric indices in an area hyperendemic for Plasmodium falciparum malaria in Gabon. The allele frequencies of the genes did not differ between the mild and the severe malaria groups. The distributions of alleles among children with distinct phenotypes of severe malaria were similar. A negative association of hypoglycaemia with the PSMB9 promoter variant PSMB9-R was found (odds ratio 0.01; chi2=12.1; P<0.0005; Pc<0.03). The promoter allele TAP1-446G was associated with hyperparasitaemia and absence of hypoglycaemia. TAP1, PSMB9, and TAP1/PSMB9 promoter alleles were in strong linkage disequilibrium. DNA sequencing of the TAP1/PSMB9 promoter region revealed a previously unrecognized single nucleotide polymorphism 455 bp upstream of the TAP1 transcription start site.